Inflammatory mediators have been widely reported in Alzheimer's disease (AD), and some 21 clinical studies to date have suggested that anti-inflammatory drugs may delay the onset or slow the progression of AD. The NIA is conducting a multicenter trial of an anti-inflammatory. Several major pharmaceutical and biotech firms are pursuing AD inflammation-related strategies. Much still remains to be done, however, to elucidate specific mechanisms. Moreover, how inflammation is sustained over a disease course of a decade or more, despite abundant evidence that inflammation-quenching mechanisms are upregulated in AD, is a question that virtually no one has addressed. In this application we put forward an overall hypothesis for how inflammation might arise, be sustained, and cause neurodegeneration in AD. This hypothesis is divided into three specific aims: induction of pro-inflammatory molecules by AD pathology; neurotoxic actions of the pro-inflammatory molecules; and completing the loop between the pro-inflammatory molecules and AD pathology. In the first specific aim we will evaluate and demonstrate mechanisms for the induction of three major inflammatory classes as the result of exposure to Abet and neurofibrillary tangle material (NFTs). In the second specific aim we will evaluate and demonstrate mechanisms for the neurotoxicity of these Abeta/NFT-mediated inflammatory processes. In the third specific aim we will evaluate and demonstrate mechanisms by which AD inflammation feeds back to further foment Abeta production, yielding the potential for a vicious cycle. Included in the preliminary data underlying these aims are three new findings: Abeta increases AD microglial expression of complement, cytokines, and apoE; NFTs activate complement in an antibody-independent fashion; and complement component C1q increases APP internalization and Abeta secretion by as much as 10-fold, putatively by blocking alpha-secretase cleavage. These novel interactions between pro-inflammatory molecules and AD pathology can help inform inflammation-related therapeutic approaches now being pursued by industry and, in particular, may provide insights to novel agents that might inhibit AD brain inflammation while leaving intact peripheral inflammatory processes (some of which are beneficial) (e.g., immune complex clearance).